Skip to main content
main-content

28.08.2018 | Original Communication | Ausgabe 11/2018 Open Access

Journal of Neurology 11/2018

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Zeitschrift:
Journal of Neurology > Ausgabe 11/2018
Autoren:
Joshua J. Todd, Vatsala Sagar, Tokunbor A. Lawal, Carolyn Allen, Muslima S. Razaqyar, Monique S. Shelton, Irene C. Chrismer, Xuemin Zhang, Mary M. Cosgrove, Anna Kuo, Ruhi Vasavada, Minal S. Jain, Melissa Waite, Dinusha Rajapakse, Jessica W. Witherspoon, Graeme Wistow, Katherine G. Meilleur
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00415-018-9033-2) contains supplementary material, which is available to authorized users.

Abstract

Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag als Mediziner

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

Neuer Inhalt

e.Med Neurologie & Psychiatrie

Kombi-Abonnement

Mit e.Med Neurologie & Psychiatrie erhalten Sie Zugang zu CME-Fortbildungen der Fachgebiete, den Premium-Inhalten der dazugehörigen Fachzeitschriften, inklusive einer gedruckten Zeitschrift Ihrer Wahl.

Weitere Produktempfehlungen anzeigen
Zusatzmaterial
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 11/2018

Journal of Neurology 11/2018 Zur Ausgabe

Neu im Fachgebiet Neurologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Neurologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise